Cinacalcet, chemically designated as N-[1-(R)-(−)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. It is disclosed in following patents U.S. Pat. Nos. 6,211,244; 6,011,068; 6,313,146 and 6,031,003.
Sensipar® (cinacalcet) is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
U.S. Pat. Nos. 6,011,068; 6,211,244 and 6,313,146 describe cinacalcet base and its pharmaceutically acceptable salts but do not provide any example for its preparation.
Several processes have been reported for the preparation of the cinacalcet base, its derivatives and pharmaceutically acceptable salts thereof.
Drugs (2002), 27(9), 831-836 discloses a synthetic scheme for preparing cinacalcet which is also disclosed as a general procedure in U.S. Pat. No. 6,211,244. The process involves reaction of 3-[3-(trifluoromethyl)phenyl]propionaldehyde prepared by Swern oxidation of the corresponding alcohol with (R)-1-(1-naphthyl)ethylamine in the presence of titanium isopropoxide to give imine which upon reduction gives cinacalcet base. However, the use of highly inflammable and toxic titanium isopropoxide in this process limits its practicability on the industrial scale.
In accordance with U.S. Pat. No. 6,211,244, cinacalcet may also be prepared by reacting 1-acetylnaphthalene with 3-3-[-(trifluoromethyl)phenyl]propylamine in the presence of titanium isopropoxide, followed by reduction using sodium cyanoborohydride and resolution of the resulting recemic cinacalcet base by chiral liquid chromatography. U.S. Pat. No. 6,211,244 also discloses reaction of 3-trichlorocinnamoylnitrile and (R)-1-naphthylethylamine in the presence of diisobutylaluminium hydride (DIBAL) followed by the reduction of the imine intermediate to produce cinacalcet. Diisobutylaluminium hydride is inflammable and not ideal for the commercial scale up.
The process outlined in U.S. Pat. No. 7,393,967 involves combining 1-bromo-3-(trifluoromethyl)benzene with N-[(1R)-1-(naphthalen-1-yl)ethyl]prop-2-en-1-amine in the presence of a catalyst and a base. However, the reaction is carried at a high temperature for about 3 to 24 hours.
The subsequent U.S. Application Publication No. 2009/0137837 describes the process for the preparation of cinacalcet involving allylic amination of 1-[3-(3-trifluoromethyl)phenyl]propene with (R)-1-naphthylethylamine in the presence of transition metal catalyst followed by the reduction. This process involves the use of expensive palladium and platinum catalyst for the condensation and column chromatography for the isolation of intermediates.
Thus there is a need in the art for an improved process for the preparation of cinacalcet which employs less expensive, easily available and environment friendly reagents.